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and interact with hundreds of different GPCRs. 12,14 Even this striking ver-
satility is only half of the story—in addition to receptors, arrestins bind
dozens, 12 and possibly hundreds, 15 of amazingly diverse proteins, serving
as multifunctional signaling organizers in the cell (see Chapter 1 ).
2. WHAT THE CRYSTAL STRUCTURE REVEALS,
AND WHAT IT DOES NOT
Visual arrestin-1 was the first subtype discovered, 2 functionally char-
acterized, 4 cloned, 16 and crystallized. 17,18 The structure revealed a unique
fold: an elongated molecule consisting of two cup-like domains with similar
cores, each organized as a seven-strand b -sandwich ( Fig. 3.1 ). Subsequently
solved structures of arrestin-2, 19,21 arrestin-3, 20 and arrestin-4 22 and even
the short splice variant of arrestin-1 23 showed rather disappointing similarity,
offering surprisingly few clues regarding the structural underpinnings of the
functional diversity of these proteins.
Several features revealed by X-ray crystal structure matched the predic-
tions of previous mutagenesis studies surprisingly well. The N-terminal half
of the molecule that was predicted to be a separable independently folding
unit 24,25 turned out to be the N-domain 17,18 ( Fig. 3.1 ). Predicted interac-
tion between the N- and C-termini 26 was also revealed. 18 A molecule con-
sisting of two domains with relatively few contacts between them appeared
poised for a global conformational rearrangement predicted by the model of
sequential multisite mechanism of receptor binding. 25 Finally, Arg175,
predicted to interact with a negatively charged partner in arrestin and func-
tion as the phosphate sensor, 27,28 was found in an unusual (for a soluble pro-
tein) arrangement of solvent-excluded charged residues in the interface
between the two domains, which was termed the “polar core”. 18,29
However, the structures solved thus far reveal only the basal conforma-
tion of all arrestin subtypes. Several lines of evidence suggest that the struc-
ture of “active” receptor-bound arrestin is likely to be quite different
(reviewed in Refs. 30,31 ) and indicate that arrestins can assume yet another
distinct conformation favorable for the binding to microtubules. 32-35 Both
still remain to be elucidated.
Crystal structure of rhodopsin 36 and its subsequent refinements, 37-39
followed by a flurry of remarkably similar structures of nonvisual
GPCRs, 40-54 raised another interesting question: how does arrestin, with
the long axis of
75 ˚ , fit GPCRs with a diameter of
40 ˚ ?
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